1. A novel small molecule inhibitor of MRCK prevents radiation-driven invasion in glioblastoma
- Author
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Abdulrahman Hussain Qaisi, William M. Holmes, Diane Crighton, Richa Vasan, Mokdad Mezna, Alexander W. Schüttelkopf, Laura McDonald, Joanna Birch, Martin Drysdale, Ariadni Kouzeli, Heather McKinnon, Duncan McArthur, Kathryn Gill, Christopher H. Gray, Justin Bower, Mairi Sime, Jennifer Konczal, Patricia McConnell, Lesley Gilmour, Antoine Vallatos, Karen Strathdee, Daniel R. Croft, Michael F. Olson, and Anthony J. Chalmers
- Subjects
0301 basic medicine ,Cancer Research ,Myosin Light Chains ,medicine.medical_treatment ,Brain tumor ,Motility ,Mice, Nude ,Antineoplastic Agents ,CDC42 ,Myosins ,Myotonic dystrophy ,Myotonin-Protein Kinase ,03 medical and health sciences ,Mice ,Myosin-Light-Chain Phosphatase ,0302 clinical medicine ,RNA interference ,Cell Movement ,Cell Line, Tumor ,Medicine ,Animals ,Humans ,Neoplasm Invasiveness ,RNA, Small Interfering ,Effector ,Kinase ,business.industry ,Brain Neoplasms ,medicine.disease ,Actins ,Radiation therapy ,030104 developmental biology ,Phenotype ,Oncology ,Microscopy, Fluorescence ,030220 oncology & carcinogenesis ,Cancer research ,Female ,RNA Interference ,business ,Glioblastoma ,Cardiac Myosins - Abstract
Glioblastoma (GBM) is an aggressive and incurable primary brain tumor that causes severe neurologic, cognitive, and psychologic symptoms. Symptoms are caused and exacerbated by the infiltrative properties of GBM cells, which enable them to pervade the healthy brain and disrupt normal function. Recent research has indicated that although radiotherapy (RT) remains the most effective component of multimodality therapy for patients with GBM, it can provoke a more infiltrative phenotype in GBM cells that survive treatment. Here, we demonstrate an essential role of the actin-myosin regulatory kinase myotonic dystrophy kinase-related CDC42-binding kinase (MRCK) in mediating the proinvasive effects of radiation. MRCK-mediated invasion occurred via downstream signaling to effector molecules MYPT1 and MLC2. MRCK was activated by clinically relevant doses per fraction of radiation, and this activation was concomitant with an increase in GBM cell motility and invasion. Furthermore, ablation of MRCK activity either by RNAi or by inhibition with the novel small-molecule inhibitor BDP-9066 prevented radiation-driven increases in motility both in vitro and in a clinically relevant orthotopic xenograft model of GBM. Crucially, treatment with BDP-9066 in combination with RT significantly increased survival in this model and markedly reduced infiltration of the contralateral cerebral hemisphere. Significance: An effective new strategy for the treatment of glioblastoma uses a novel, anti-invasive chemotherapeutic to prevent infiltration of the normal brain by glioblastoma cells.Cancer Res; 78(22); 6509–22. ©2018 AACR.
- Published
- 2018